Cross-sectional studies suggest that the menopause is associated with changes in endocrine-metabolic function and body composition that may accelerate the development of osteoporosis and cardiovascular disease. The hypotheses of this longitudinal study are that the menopausal transition is associated with change before the cessation of menses as described: 1) decreases in nocturnal secretory profile of growth hormone, that in combination with the decreases in ovarian sex hormones, contribute to changes in body composition, specifically decreases in bone mass and increases in fat mass, 2) increases in biochemical markers of bone turnover that are measured in blood and urine that predict decreases in bone mass, and 3) increases in body fat mass and fat distribution to the intra-abdominal area that are associated with adverse changes in lipid and lipoprotein profiles. The women are 110 healthy, nonsmoking female participants of the Baltimore Longitudinal Study of Aging (BLSA), ages 45-55 years who are experiencing monthly menses at enrollment. They receive quarterly GCRC outpatient visits until menses have ceased for 2 years. The visits include a menopausal symptom questionnaire, endocrine and blood lipid profiles, anthropometry, dual energy x-ray absorptiometry (DEXA), bone biochemistries, and dietary assessments. As of November 30, 1997, 104 women have completed 956 outpatient visits. We have performed preliminary analyses of longitudinal data of bone mineral density (BMD) at the lumbar spine and hip. As of April 1997, 27 women who remain premenopausal (PRE), defined as midfollicular phase plasma FSH levels all <30mU/ml, were followed >1 year (mean 2.5 years), and had a mean age of 48.7 +/-0.3 years. They were compared to 21 women classified as perimenopausal (PERI), defined as at least one plasma FSH >30mU/ml with at least one visit >0.3 years before (mean 0.84 years) and at least one visit >1 year after (mean 1.90 years) the initial high FSH value. They were followed an average of 2.7 years, with a mean age of 50.3+/- 0.6 years. The PRE group had a significant increase in BMD in the spine (1.7+/- 0.7%, *p<.05 vs baseline), while the PERI group had a sifnificant decrease (-2.7+/- 1.1%, p<.05 vs baseline), and was significantly different than the PRE group (p<.002). Both the PRE and the PERI groups were significantly losing bone at the femoral neck (-4.3+/- 1.2%, -6.5+/- 1.4% respectively) and trochanteric region (-4.0+/- 1.1%, -6.9+/- 1.6%, p<.002 vs baseline). There was no significant difference between PRE and PERI in any hip site. These data reveal the expected accelerated vertebral bone loss during the perimenopausal transition, whereas the similar losses of hip BMD in pre- and perimenopausal women appear not to be distinguishable by the reproductive hormone milieu. Data analyses are underway to determine if serial changes in biochemical markers of bone turnover correlate with changes in bone density. Body composition is measured by DEXA and anthropometrics. As of April 1997, complete body composition data are available for 21 women who remain premenopausal and 24 who are classified as perimenopausal, as defined above. None of the parameters of body composition measured (weight, body mass index, (BMI), waist circumference, waist-hip ratio (WHR), total fat mass by DEXA scan, or % fat) differed by ANOVA comparing premenopausal and perimenoapusal groups at baseline. Perimenopausal women, in contrast to the premenopausal group, exhibit significant increases in the estimates of fatness (total fat and % fat by DEXA, p<0.03 by ANOVA comparing premenopausal and perimenopausal deltas), in fat distribution (waist circumference and WHR, p<0.05), and in serum leptin levels (p<0.03), but not in weight or BMI. These data suggest that changes in body composition may occur early in the menopausal transition as defined by a serum FSH level >/- 30 mU/mL. As of November 30, 1997, 14 premenopausal women have compeletd the first of three pairs of overnight visits for study of growth hormone by frequent blood sampling. Two of these 14 women have begun the menopausal transition based on elevation of plasma FSH level and irregularity of menses and have completed the second set of overnight visits. A preliminary analysis of the longitudinal data will be performed when plasma FSH levels are greater than 30 mU/mL in 6 of the women. In January 1998, we recrutied an additional premenopausal woman for the overnight visits, thus completing the study cohort of 15 women. Future plans include the continued characterization of the biological antecedents and sequelae of the menopausal transition. Biochemical markers of bone and cardiovascular disease risk will be studied so as to target hormone replacement therapy to those women who are most likely to benefit. Moreover, the continued longitudinal assessment of the BLSA cohort beyond that provided in this proposal will permit an evaluation of the effects of the menopausal transition on age-related disease in women.